Polymerisation initiator and use

ABSTRACT

The application discloses supported initiators for transition metal medicated living free radical and/or atom transfer polymerisation comprising an initiator moiety attached to a support via a selectively cleavable link, and their use to produce polymers.

[0001] The current application relates to supported polymerisationinitiators and their use to produce polymers.

[0002] Transition metal-mediated living radical polymerization hasdeveloped as an efficacious technique for the controlled polymerizationof (meth)acrylic and styrenic monomers under free-radical-likeconditions. A wide variety of transition metal complexes/ligand havealready been reported^(1,2,3,4,5,6,7,8,9,10,11). This chemistry isrelatively easy to carry out, and very robust with tolerance to mostfunctional groups which may be present in reagents or due to impurities.These types of polymerisations lead to an unprecedented range ofcontrolled architecture polymers including star polymers^(12, 13, 14),block copolymers^(15, 16, 17), polymer brushes^(18, 19), amphiphilicpolymers²⁰, glycopolymers²¹, etc. One of the major drawbacks of thischemistry is the high levels of transition metal salt used with oftenequimolar concentrations required with respect to initiator causingreaction solutions to be highly colored usually necessitating asecondary process for catalyst removal. A number of strategies have beenreported to alleviate this problem including immobilization of thecatalyst on insoluble supports^(22, 23, 24), e.g. silica gel and the useof fluorous biphase reaction media²⁵ which allow efficient separation ofthe catalyst and for the potential for catalyst recycling.

[0003] The use of insoluble supports to mediate organic transformationshas been developed extensively over recent years. In particularcombinatorial and fast throughput synthesis techniques have becomecommonplace whereby the organic substrate is transformed whilstimmobilized prior to cleavage and subsequent recovery. Indeed this isthe basis for automated peptide synthesis that is routinely carried outby solid phase synthetic methods based on sequential addition of aminoacids to an insoluble crosslinked polymeric support. This chemistry hasgrown from the pioneering work of Merrifield²⁶ with “Merrifield”chloromethyl functionalised beads being utilized for more than 20 yearsfor the synthesis of medium sized peptide using the Boc strategy.Probably the most utilized solid supported poly(peptide) synthesis isnow based on Fmoc chemistry for routine peptide synthesis. The mostcommonly used resin for Fmoc chemistry is Wang resin²⁷ which is alsobased on crosslinked poly(styrene) onto which an acid-labile linker hasbeen attached allowing cleavage of products by a simple acid wash. Theavailable functional group on the Wang resin is a benzylic alcohol, witha range of loadings/resin types readily available. This chemistry can becarried out in batch and continuous and as such Wang resin chemistry hasbeen extensively developed. Although this chemistry is now consideredalmost routine for the synthesis of certain biological polymers (orsynthetic polymers with biological activity). The inventors havedeveloped the transformation of hydroxyl groups into activated alkylhalide based initiators for living radical polymerisation forhomogeneous reactions²⁸; the inventors envisage that they, would be ableto take advantage of the tremendous advances made in resin developmentfor biological polymer synthesis.

[0004] Supported polymer synthesis, as opposed to supported catalysise.g. Ziegler-Natta polymerisation, is most ideally suited to additionpolymerisation, which precludes the need for addition, and removal ofprotecting groups facilitating the synthesis. The main reason for thisnot being carried out to date is probably that living chainpolymerisation would be required and most living polymerisationchemistry is not tolerant of most functional groups and or proticimpurities routinely present in solvents and other reagents²⁹.

[0005] The use of polymeric solid support (resin beads) for organicsynthesis relies on three interconnected requirements: preferably, i) across-linked insoluble but solvent swellable polymeric material that isinert to the conditions of synthesis. ii) some means of linking the tothe solid phase that permit selective cleavage to give the finalproduct, iii) a successful synthetic procedure compatible with thelinker and the solid phase. One of the most commonly available resinused is Wang resin which is based on cross-linked polystyrene onto whicha 4-hydroxybenzyl alcohol moiety has been attached (Scheme 1).

[0006] Synthesis of a solid support initiator based on Wang resin forATP of methacrylates.

[0007] It seems that Wang resins are ideally suited to functionalisationwith functionality suitable for living radical polymerisation. This thenallows for polymers to be grown from the surface of the resin prior towashing out the catalyst/excess monomers and cleavage of the product soas to harvest relatively pure polymers. The potential for automatingthis process is also attractive. The main advantage of this approach isthe elimination of excess of reagents by simple filtration and solventwashes. The product is isolated by cleavage, for example underrelatively mild conditions, of the ester linkage between the resin andthe copolymer.

[0008] The first aspect of the invention provides a supported initiatorfor transition metal mediated living free radical and/or atom transferpolymerisation comprising an initiator moiety attached to a support viaa selectively cleavable link.

[0009] Such a supported initiator allows polymers to be grown on thesupport and then cleaved from the support using the selectivelycleavable link. The selectively cleavable link may be any bond which maybe chemically or physically broken substantially without breaking thepolymer attached to the support. This allows the polymer to be releasedand the support separated from the polymer.

[0010] For example, the selectively cleavable link may be an acid-labilegroup such as an ester group. Such groups are selectively cleavable byusing an acid such as trifluoroacetic acid.

[0011] The initiator may be used for living free radical polymerisation,of the sort demonstrated in, for example, WO 99/28352 or atom transferpolymerisation, of the sort demonstrated in WO 96/30421.

[0012] Preferably the initiator moiety comprises an activated halogenatom. Such an atom may be defined as a halogen atom a to an electronwithdrawing group capable of stabilising a partial radical or a freeradical formed on an adjacent carbon group. The initiator moiety maycomprise a homolytically cleavable bond with a halogen atom.

[0013] Homolytically cleavable means a bond which breaks withoutintegral charge formation on either atom by homolytic fission.Conventionally this produces a radical on the compound and a halogenatom radical. For example:

[0014] However, the increase in the rate of reaction observed by theinventors with free-radical inhibitors indicates that true free-radicalsdo not appear to be formed using some of the catalysts below. It isbelieved that this occurs in a concerted fashion whereby the monomer isinserted into the bond without formation of a discrete free radicalspecies in the system. That is during propagation this results in theformation at a new carbon-carbon bond and a new carbon-halogen bondwithout free-radical formation. The mechanism involves bridging halogenatoms for example:

[0015] where:

[0016] ML is a transmission metal-diimine complex.

[0017] A “free-radical” is defined as an atom or group of atoms havingan unpaired valence electron and which is a separate entity withoutother interactions.

[0018] Preferably the halogen atom is selected from F, Cl, Br and I.

[0019] The initiator moiety may have the formula:

R¹⁷R¹⁸R¹⁹C—X

[0020] wherein:

[0021] X is selected from Cl, Br, I, OR²⁰, SR²¹, SeR²¹, OP(═O)R²¹,OP(═O)R²¹, OP(═O)(OR²¹)₂, OP(═O)O²¹, O—N(R²¹)₂ and S—C(═S)N(R²¹)₂, whereR²⁰=a C₁ to C₂₀ alkyl where one or more of the hydrogen atoms may beindependently replaced by halide, R²¹ is aryl or a straight or branchedC₁-C₂₀ alkyl group, and where an (NR²¹)₂ group is present, the two R²¹groups may be joined to form a 5- or 6-membered heterocyclic ring; and

[0022] R¹⁷, R¹⁸ and R¹⁹ are each independently selected from H, halogen,C₁-C₂₀ alkyl, C₃-C₈ cycloalkyl, C═YR²², C(═Y)NR²³R²⁴, COCl, OH, CN,C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, oxiranyl, glycidyl, aryl, heterocyclyl,aralkyl, aralkenyl, C₁-C₆ alkyl in which 1 or more hydrogen atoms arereplaced with halogen and C₁ to C₆ alkyl substituted with from 1 to 3substitutions selected from alkoxyl, aryl, heterocyclyl, C(═Y)R²²,C(═Y)NR²³R²⁴, oxiranyl and glycidyl;

[0023] where R²² is C₁ to C₂₀ alkyl, C₁ to C₂₀ alkoxy, aryloxy orheterocyclyloxy; and

[0024] R²³ and R²⁴ are independently H, C₁ to C₂₀ alkyl, or R²³ and R²⁴may be joined together to form an alkylene group of 2 to 5 carbon atoms,thus forming a 3- to 6-membered ring;

[0025] where Y may be NR²⁵ or O, and R²⁵ is H, straight or branched C₁to C₂₀ alkyl or aryl;

[0026] such that no more than two of R¹⁷, R¹⁸ and R¹⁹ are H, and whereinat least one of R¹⁷, R¹⁸ or R¹⁹ is attached to the support, optionallyvia the selectively cleavable link.

[0027] The initiator moiety may also be selected from

[0028]  where: R is independently selectable and is selected fromstraight, branched or cyclic alkyl, hydrogen, substituted alkyl,hydroxyalkyl, carboxyalkyl or substituted benzyl, wherein at least one Ris attached to the support via the selectively cleavable link; and

[0029] X is a halide.

[0030] The initiator may especially-be selected from formulae 13-23. Theinitiator may be linked via one of the carbon-containing side-chains onthe initiator to the support via a selectively cleavable link.

[0031] where:

[0032] X Br, I or Cl, preferably Br

[0033] R′=—H.

[0034] —(CH₂)_(p)R¹¹ (where m is a whole number, preferably p=1 to 20,more preferably 1 to 10, most preferably 1 to 5, R¹¹=H, OH, COOH,halide, NH₂, SO₃, COX— where X is Br, I or C) or:

[0035] R¹¹¹=—COOH, —COX (where X is Br, I, F or Cl), —OH, —NH₂ or —SO₃H,especially 2-hydroxyethyl-2′-methyl-2′ bromopropionate.

[0036] Especially preferred examples of Formula 16 are:

[0037] The careful selection of functional alkyl halides allows theproduction of terminally functionalised polymers. For example, theselection of a hydroxy containing alkyl bromide allows the production ofα-hydroxy terminal polymers. This can be achieved without the need ofprotecting group chemistry.

[0038] The supported initiator may also comprise an initiator moiety of1,1,1-trichloroacetone.

[0039] Further suitable initiators which may be attached to a supportare disclosed in WO 96/30421.

[0040] The inventors have found that changing the concentration of theinitiator on the support affects the overall kinetic of polymerisation.A concentration of initiator of less than 4 mmol g⁻¹ with respect to thetotal mass of the support produces improved PDI (polymer dispersityindex) numbers. More preferably the loading is less than 3, less than 2or less than 1 mmol g⁻¹.

[0041] Preferably the support is in the form of a sheet or bead. Beadsare especially preferable since they have a high surface area

[0042] The support may be made of an inorganic material such as silicaAlternatively, the support may be an organic material such as across-linked organic polymer. Most preferably the cross-linked organicpolymer is poly(styrene-w-divinylbenzone), especially of the sort knownas Wang resins.

[0043] It is especially preferable that the support is porous ormacroporous. This allows initiators to be produced within the supportand allows supports with a high surface area to be produced. Similarly,solvent-swellable supports are also preferable since they allow theproduction of supported initiators having a high surface area.

[0044] Most preferably the supported initiator has the formula:

[0045] where P is a polymeric support.

[0046] A further aspect of the invention provides for the use of aninitiator according to the first aspect of the invention in thesynthesis of a polymer.

[0047] A further aspect of the invention provides a method forpolymerising one or more olefinically unsaturated monomers comprisingthe steps of:

[0048] (i) providing a supported initiator according to the first aspectof the invention;

[0049] (ii) reacting the supported initiator with at least one monomerin the presence of a catalyst to form a polymer attached to the support;and

[0050] (iii) removing the support from the polymer by cleaving theselectively cleavable link.

[0051] Preferably the polymer is cleaved from the support by selectivelycleaving with acid, such as trifluoroacetic acid.

[0052] Preferably the monomer is methacrylate, acrylate or styrene.Acrylamide, methacrylamide or acrylonitrile amy also be used.Alternative monomers also include dienes such as butadiene, vinyletheror vinylacetate.

[0053] Examples of olefinically unsaturated monomers that may bepolymerised include methyl methacrylate, ethyl methacrylate, propylmethacrylate (all isomers), butyl methacrylate (all isomers), and otheralkyl methacrylates; corresponding acrylates; also functionalisedmethacrylates and acrylates including glycidyl methacrylate,trimethoxysilyl propyl methacrylate, allyl methacrylate, hydroxyethylmethacrylate, hydroxypropyl methacrylate, dialkylaminoalkylmethacrylates; fluoroalkyl (meth)acrylates; methacrylic acid, acrylicacid; fumaric acid (and esters), itaconic acid (and esters), maleicanhydride; styrene, α-methyl styrene; vinyl halides such as vinylchloride and vinyl fluoride; acrylonitrile, methacrylonitrile;vinylidene halides of formula CH₂═C(Hal)₂ where each halogen isindependently Cl or F; optionally substituted butadienes of the formulaCH₂═C(R¹⁵) C(R¹⁵)═CH₂ where R¹⁵ is independently H, C1 to C10 alkyl, Cl,or F; sulphonic acids or derivatives thereof of formula CH₂═CHSO₂OMwherein M is Na, K, Li, N(R¹⁶)₄ where each R¹⁶ is independently H or Clor alkyl, D is COZ, ON, N(R¹⁶)₂ or SO₂OZ and Z is H, Li, Na, K orN(R¹⁶)₄; acrylamide or derivatives thereof of formula CH₂═CHCON(R¹⁶)₂and methacrylamide or derivative thereof of formula CH₂═C(CH₃)CON(R¹⁶)₂.Mixtures of such monomers may be used.

[0054] Preferably, the monomers are commercially available and maycontain a free-radical inhibitor such as2,6-di-tert-butyl-4-methylphenol or methoxyphenol.

[0055] A gradient polymer may be produced by reacting the supportedinitiator with a first monomer and then adding a second monomer prior tocompletion of the polymerisation with the first monomer. Alternatively,a block polymer may be produced by reacting the supported initiator witha first monomer, removing unreacted first monomer before termination ofits polymerisation reaction; and adding a second monomer to the reactionmixture to form the block copolymer. The block copolymer is then removedfrom the resin by means of cleavage of the selectively cleavable link ineither case, the second polymer may be added at 75, 80, 85, 90 or 95%completion of the polymerisation of the first monomer.

[0056] Reaction may take place with or without the presence of asolvent. Suitable solvents in which the catalyst, monomer and polymerproducts are sufficiently soluble for reactions to occur include water,protic and non-protic solvents including propionitrile, hexane, heptane,dimethoxyethane, diethoxyethane, tetrahydrofurane, ethylacetate,diethylether, N,N-dimethylformamide anisole acetonitrile diphenylether,methylisobtyrate, butan-2-one, toluene and xylene. Especially preferredsolvents are xylene and toluene. Preferably the solvents are used atleast 1% by weight, more preferably at least 10% by weight.

[0057] Preferably the catalyst comprises a ligand which is any N-, O-,P- or S-containing compound which can coordinate in a δ-bond to atransition metal or any carbon-containing compound which can coordinatein a π-bond to the transition metal, such that direct bonds between thetransition metal and growing polymer radicals are not formed.

[0058] The catalyst may also comprise a first compound

MY

[0059] where:

[0060] M is a transition metal having an oxidation state which iscapable of being oxidised by one formal oxidation state,

[0061] Y is a mono, divalent or polyvalent counterion.

[0062] The catalyst may also be defined by the formula:

[ML_(m)]^(n+)A^(n−)

[0063] where:

[0064] M=a transition metal having an oxidation state which is capableof being oxidised by one formal oxidation state,

[0065] L=an organodiimine where at least one of the nitrogens of thediimine is not part of an aromatic ring,

[0066] A=anion,

[0067] n=integer of 1 to 3,

[0068] m=an integer of 1 to 2.

[0069] The metal ion may be attached to a coordinating ligand, such as(CH₃CN)₄. Y may be chosen from Cl, Br, F, I, NO₃, PF₆, BF₄, SO₄, CN,SPh, SCN, SePh or triflate (CF₃SO₃). Copper (I) triflate may be used.This is available in the form of a commercially available benzenecomplex (CF₃SO₃Cu)₂C₆H₆. The especially preferred compound used is CuBr.

[0070] A may be F, Cl, Br, I, N, O₃, SO₄ or CuX₂ (where X is a halogen).

[0071] The transition metal may be selected from Cu¹⁺, Cu²⁺, Fe²⁺, Fe³⁻,Ru²⁺, Ru³⁺, Cr²⁺, Cr³⁺, Mo²⁺, Mo³⁺, W²⁺, W³⁺, Mn³⁺, Mn⁴⁺, Rh³⁺, Rh⁴⁺,Re²⁺, Re³⁺, Co⁺, Co²⁺, V²⁺, V³⁺, Zn⁻, Zn²⁺, Au⁺, Au²⁺, Ag⁺ and Ag²⁺.

[0072] Preferably the organodiimine has a formula selected from:

[0073] 1,4-diaza-1,3-butadiene

[0074]  a 2-pyridinecarbaldehyde imine

[0075] or a Quinoline Carbaldehyde

[0076] where R₁, R₂, R₁₀, R₁₁, R₁₂ and R₁₃ may be varied independentlyand R₁, R₂, R₁₀, R₁₁, R₁₂ and R₁₃ may be H, straight chain, branchedchain or cyclic saturated alkyl, hydroxyalkyl, carboxyalkyl, aryl (suchas phenyl or phenyl, substituted where substitution is as described forR₄ to R₉), CH₂Ar (where Ar=aryl or substituted aryl) or a halogen.Preferably R₁, R₂, R₁₀, R₁₁, R₁₂ and R₁₃ may be a C₁ to C₂₀ alkyl,hydroxyalkyl or carboxyalkyl, in particular C₁ to C₄ alkyl, especiallymethyl or ethyl, n-propylisopropyl, n-butyl, sec-butyl, tert butyl,cyclohexyl, 2-ethylhexyl, octyl decyl or lauryl.

[0077] R₁, R₂, R₁₀, R₁₁, R₁₂ and R₁₃ may especially be methyl.

[0078] R₃ to R₉ may independently be selected from the group describedfor R₁, R₂, R₁₀, R₁₁, R₁₂ and R₁₃ or additionally OCH_(2n+1), (where nis an integer from 1 to 20), NO₂, CN or O═CR (where R=alkyl, benzylPhCH₂ or a substituted benzyl, preferably a C₁ to C₂₀ alkyl, especiallya C₁ to C₄ alkyl).

[0079] Furthermore, the compounds may exhibit a chiral centre α to oneof the nitrogen groups. This allows the possibility for polymers havingdifferent stereochemistry structures to be produced.

[0080] Compounds of general Formula 25 may comprise one or more fusedrings on the pyridine group.

[0081] One or more adjacent R₁ and R₃, R₃ and R₄, R₄ and R₂, R₁₀ and R₉,R₈ and R₉, R₈ and R₇, R₇ and R₆, R₆ and R₅ groups may be C₅ to C₈cycloalkyl, cycloalkenyl, polycycloalkyl, polycycloalkenyl orcyclicaryl, such as cyclohexyl, cyclohexenyl or norborneyl.

[0082] Preferred ligands include:

[0083] Preferred ligands include:

[0084] R14=Hydrogen, C₁ to C₁₀ branched chain alkyl, carboxy- orhydroxy-C₁ to C₁₀ alkyl.

[0085] Preferably the catalyst is

[0086] with Cu Br

[0087] Most preferably the initiator has the general formula:

[0088] where P is a polymeric support.

[0089] The amount of the initiator loading on the support preferably isless than 4 mmol g⁻¹, with respect to the total mass of the support, ofinitiating sites. More preferably the amount of loading is less than 4,most preferably less than 2, especially less than 1 mmol g⁻¹ ofinitiating sites. Preferably the minimum amount of initiator is 0.01mmol/g

[0090] The invention further provides a method for synthesizing asupported initiator as defined according to the first aspect of theinvention comprising the steps of:

[0091] (i) providing a support having one or more reactive groups; and

[0092] (ii) reacting the support with an initiator precursor to form thesupported initiator.

[0093] Preferably, the support has formula:

S—OH where S is the support

[0094] and the initiator precursor has formula:

I-Hal, where I is the initiator and Hal is a halogen,

[0095] and the halogen and hydroxyl groups react to form formula:

S—O—I

[0096] The method preferably comprises reacting:

[0097] to form a supported initiator of formula:

[0098]  where the arrow indicates the site of the selectively cleavablelink.

[0099] A still further aspect of the invention provides supportedinitiators according to the first aspect of the invention additionallycomprising a polymer extending from the initiator moiety.

[0100] The invention will now be described by way of example only withreference to the following figures

[0101]FIG. 1. FT-IR spectra overlay of the Wang resin before (dash line)and after (straight-line) esterification reaction.

[0102]FIG. 2. Solid state NMR of Wang resin supported initiator.

[0103]FIG. 3. Evolution of M_(n) with conversion for the solid supportpolymerization of MMA at 90° C. in presence of 60% v/v toluene with³²/[I]=100.

[0104]FIG. 4. First order kinetic plot for the solid supportpolymerization of MMA at 90° C. in presence of 60% v/v toluene with³²/[I]=100.

[0105]FIG. 5. SEC traces of PMMA following the value of resin load andthe percentage of dilution.

[0106]FIG. 6. ¹H NMR of final copolymer PMMA-b-PbzMA.

[0107]FIG. 7. Solid state NMR of PMMA supported on Wang resin.

[0108]FIG. 8. Scanning Electron Microscopy of (a) Wang resin initiator,(b) PMMA attached to the resin (conversion=34%), (c) PMMA attached tothe resin (conversion 87.6%) and (a) PMMA-b-PbzMA (Run 5).

EXPERIMENTAL SECTION

[0109] General Information.

[0110] Methyl methacrylate (MMA) and benzylmethacrylate (BzMA), suppliedby Aldrich (99%) were purified by passing through a column of activatedbasic alumina to remove inhibitor. CuBr, triethylamine,2-bromo-iso-butyryl bromide, trifluoroacetic acid (Lancaster), toluene(Fisons, 99.8%) and tetrahydrofuran (BDH) were used as received.N-(n-propyl)-2-pyridylmethanimine ligand was synthesized as previouslydescribed. Wang resin was supplied by Zeneca in a range of differentload (1 to 4 mmol.g⁻¹ of OH functions, range of size 150-300 μm).

[0111] Before polymerization, all solvents, monomers and other reagentswere degassed via a minimum of three freeze-pump-thaw cycles. Allmanipulations were carried out under a nitrogen atmosphere usingstandard schlenk or syringe techniques.

[0112] Synthesis of Wang Resin Initiator.

[0113] In a 250 mL three neck flask, equipped with a mechanic stirrer,was added 10 g of Wang resin (1×10⁻² mol, 1 mmol.g⁻¹ OH functions) and150 mL of tetrahydrofuran. Then, 1.6 mL (1.1 eq) of triethylamine and1.4 mL of 2-bromo-iso-butyryl bromide (1.1 eq) was added dropwise. Themixture was kept under slow stirring (80 mph) overnight and nextfiltrate. The insoluble phase was put in another flask in presence ofdeionized water and kept under mechanical stir during 5 hours toeliminate completely triethylammonium salts. The Wang resin initiatorwas recover by filtration and dry under vacuum. FT-IR (ATR)ν_(max).cm⁻¹: appearance at 1730 (C═O vibration) and disappearance ofhydroxyl functions at 3100-3500. NMR ¹H (CDCl₃, 300 MHz) δ_(ppm): broadpeaks. NMR ¹³C (CDCl₃, 300 MHz) δ_(ppm): 163.5 (C═O), 130.33 and 115.25(aromatics carbons), 60.84 (C—Br), 31.24 (CH₃).

[0114] Homopolymerization Procedure.

[0115] A typical polymerization procedure is as follow. In a 250 mLthree neck flask, equipped with a mechanic stirrer, was added undernitrogen, 1 g of Wang initiator (1 mmol.g⁻¹, 1×10⁻³ mol) and 143 mg ofCuBr (1 eq, 1×10⁻³ mol). In a schlenk tube was prepared a solution of 10mL of methylmethacrylate (MMA) (M_(a)=10000 g.mol⁻¹ targeted), 15 mL ofanhydrous toluene (60% v/v) and 0.3 mL ofN-(n-propyl)-2-pyridylmethanimine (2 eq, 2×10⁻³ mol). Oxygen was removedby three freeze-pump-thaw cycles and the solution added to the flask bysyringe. The mixture was kept at 90° C. under constant stirring (145mph). After a certain time, the charge was cooled and diluted withtetrahydrofuran. The polymer attached to the resin was recovered byfiltration and then washed successively with THF, dichloromethane andmethanol to remove the excess of ligand and copper. The molecular weightof the PMMA was obtained by cleavage under mild conditions of the esterlink between the resin and the polymer.

[0116] Cleavage Procedure.

[0117] 500 mg of the previous polymer was put in a 100 mL flask followedby 10 mL of dichloromethane. Then 10 mL of trifluoroacetic acid wasadded dropwise. The mixture was kept under stirring at room temperaturefor 5 hours. The PMMA present in the dichloromethane phase was recoveredafter filtration, evaporation of the solvent and precipitation inmethanol. NMR ¹H (CDCl₃, 300 MHz) δ_(ppm): 0.7-1.1 (CH₃), 1.6-2.1 (CH₂),3.6 (OCH₃).

[0118] Block Copolymerization Procedure.

[0119] This is exemplified in Scheme 2:

[0120] Synthesis of PMMA-b-PBzMA block copolymers by ATP using solidsupport initiator.

[0121] Synthesis of PMMA-b-PBzMA block copolymers by ATP using solidsupport initiator.

[0122] a) continuous process: gradient copolymer. The first block ofPMMA was synthesized as previously described. After a certain time at90° C. (80% conversion of MMA/4 h), 10 mL of benzylmethacrylate(M_(n)=g.mol⁻¹ targeted) was added under nitrogen flow and the mixturewas stirred at 90° C. for a certain time. The charge was then cooled andthe block copolymers attached to the resin recovered after washing withTHF, dichloromethane and methanol.

[0123] b) two steps process: block copolymer. The first block of PMMAwas synthesized as previously described. After a certain time at 90° C.(80% conversion of MMA/4 h), the flask was cooled at room temperature.The liquid phase was removed under nitrogen stream with filter canulaand the beads washed four times with degassed toluene. After completeelimination of residual MMA, 143 mg of CuBr was added followed by adegassed solution composed of 15 mL of toluene, 10 mL ofbenzylmethacrylate and 0.3 mL of N-(n-propyl)-2-pyridylmethanimine.Then, the mixture was reheated at 90° C. for a certain time. The chargewas then cooled and the block copolymers attached to the resin recoveredafter washing with THF, dichloromethane and methanol.

[0124] Characterizations.

[0125]¹H and ¹³C solid state NMR spectroscopy of the compounds attachedto the Wang resin were carried out on a 300 MHz Bruker NMR whereas ¹HNMR of the final block copolymer was carried out in CDCl₃ solution on aBrücker-DPX 300 MHz instrument.

[0126] Molecular weight and molecular weight distribution ofhomopolymers and block copolymers were measured by Size ExclusionChromatography on a system equipped with a guard column, 2 mixed Dcolumns (Polymer Laboratories), with both DRI and UV detectors andeluted with tetrahydrofuran at 1 mL.min⁻¹. Molecular weight wascalculated against narrow PMMA standards for DRI and PS standards forUV. Polymer conversion were measured by gravimetry after drying the in avacuum oven.

[0127] DSC of the final block copolymers was carried out on a Perkin.Elmer Pyris 1 instrument. Samples underwent 3 heating and cooling stagesuntil final measurements was made between 0 and 150° C. at a heatingrate of 20° C.min⁻¹.

[0128] FTIR spectra of the Wang resin and Wang initiator were recordedon a Brücker VECTOR 22 instrument with fitted an attenuated totalreflection (ATR) cell.

[0129] Scanning electron microscopy (SEM) of the resin compounds wascarried out on a JEOL JSM-6100. The residual copper analysis wasdetermined using a Leeman Labs inductively coupled plasma atomicemission spectrophotometer (ICP-AES) calibrated with Leeman Labs ICPstandards.

[0130] Results and Discussion

[0131] Initiator Synthesis.

[0132] Initiator functionalized beads were synthesized from thecondensation reaction of Wang resin with a range of hydroxyl loadings(from 1 to 4 mmol g⁻¹ of 4-hydroxybenzyl alcohol functionality) and2-bromo-iso-butyrylbromide, by esterification reaction in presence oftriethylamine, in tetrahydrofuran suspension at room temperature. Thistype of tertiary bromide has been widely used for the efficientinitiation of living radical polymerisation of various methacrylateswith copper (1) bromide in conjunction with alkylpyridylmethanimineligands. The supported initiator was characterized by FT-IR, gel-phaseNMR and cross polarization magic angle spinning (CP/MAS) NMRspectroscopy. Acylation of the resin hydroxyl group by the acyl bromideis observed by the disappearance of the hydroxyl stretch, 3450 cm⁻¹,accompanied by the appearance of an intense signal at 1730 cm⁻¹ (FIG.1). Acceptable ³C NMR spectra can be obtained at 300 MHz by swelling thebeads in CDCl₃ and obtaining spectra under conventional solution NMRconditions, gel phase NMR. Gel Phase NMR shows the presence of theinitiator moiety, more mobile as compared to the polystyrene core of thebeads, with the methyl group, 31.2 ppm, tertiary carbon (—CBr), 60.8 ppmand the carbonyl from the ester, 163 ppm, as would be expected forsolution NMR. The polystyrene resin is not observed by this method.CP-MAS solid state NMR study of the resin bound initiator showed thepresence of the polystyrene as a broad peak centered around 120 ppm aswell as other characteristic peaks (see Figure). The resin was alsocharacterized by scanning electron microscopy (SEM), which shows thespherical nature of the support retained with the size of the beads inthe range of 150 to 200 μm as expected according to the data given bythe supplier.

[0133] Impact of the Resin Load.

[0134] During this study, the load of the resin was revealed as animportant parameter to consider because of his influence over themolecular weight distribution of the final polymer. Two differentloadings of resin were utilized to prepare as initiators, 4 mmol g⁻¹ and1 mmol g⁻¹ of initiating sites so as to investigate the impact of thisparameter on the overall kinetic of polymerization. It is noted thatsupported organic transformations are normally carried out at the lowerloadings with higher loading often causing complications due to sidereactions. Table 1 reports polymerisation results from these initialexperiments. At a loading of 4 mmol g−1 high conversions are reached at50% v/v concentration after 3 hours. However, at higher dilution, 10%v/v less than 20% conversion is seen after 9 hours. At high dilution animprovement in the PDI of the product is observed but remainsapproximately 1.3. On decreasing the loading of the initiator over 60%conversion is attained after 3 hours with the cleaved PMMA showing anexcellent Pdi of 1.18. At 4 mmol g⁻¹ it is envisaged that a high amountof termination occurs due to the close proximity of the propagatingchains which would also provide steric constraints within the reaction.A loading of 1 mmol g⁻¹ leads to excellent product and all furtherexperiments were carried out on 1 mmol g⁻¹ resins. FIG. 5 shows the SECtraces of the final polymers from different loading experiments. Asymmetrical peak with a PDI of 1.18 (conversioni=62%, 3 hours) in 60%v/v of solvent is seen for 1 mmol g⁻¹. PDI increases from 1.18 to 1.36at 87% of MMA conversion and 1.78 at 93%, Table 1. This increase in PDIis attributed to the increase in viscosity of the reaction medium aboveapproximately 90% conversion which results in inefficient agitation.TABLE 1 Resin load impact Resin load Solvent Time Conversion^(a)) Run(mmol.g⁻¹) % v/v (h) % PDI 1 4 50 3 80 1.80 2 4 90 5 10 1.32 3 4 190  915 1.30 4 1 60 3 61.9 1.18

[0135] Cleavage of the Polymer Product from the Resin

[0136] In order to follow the polymerization reactions it was necessaryto cleave the products from the resin support at their point ofattachment. The detached polymer chains could be then analyzed usingstandard techniques such as size exclusion chromatography (SEC) and NMR,to obtain molecular weight, polydispersity and structural information.The attachment via a benzylic ester linkage allows for the cleavage ofthe polymer products from the resin support by reaction with an excessof trifluoroacetic acid (TFA). It is noted that the hydrolysis of thebackbone ester groups of the polymer e.g. PMMA does not occur by thistreatment as attested by ¹H NMR spectra that confirm the presence of the—OCH₃ group, 3.5 ppm, in the final polymers.

[0137] Homopolymers.

[0138] Polymerization of methyl methacrylate in presence of Wang resinsupported initiator was carried out in toluene solution. An importantfactor, which has to be considered in solid phase organic synthesis, isthe swelling of the hydrophobic matrix. Cross-linking polystyrene swellsin apolar solvents as toluene or dichloromethane, which allow a highermobility and availability of the initiating sites to the copper/ligandcatalyst and thus increases the efficiency of the initiation. Thepolymerisation kinetics were followed in 60% v/v of toluene at 90° C.with a resin loading of 1 mmol g⁻¹. The M_(n) of the PMMA increasesreasonably linearly with conversion (FIG. 3, Table 2), consistentlyslightly above the theoretical M_(n) as is often the case with this typeof polymerisation under homogeneous conditions⁹. The first order kineticplot shows a straight line indicating that the concentration of activescenters remains constant during the polymerization reaction (FIG. 4,Table 2). Under these conditions, the polydispersity of the productobtained is less than 1.3. This result is similar to PMMA obtained frompolymerization mediated by silica gel supported catalyst²² andpolymerisation under fluorous biphasic conditions²⁰. TABLE 2 PMMAhomopolymer Time Conversion M_(n) exp^(a)) M_(n) theo^(b)) (h) (%)(g.mol⁻¹) (g.mol⁻¹) PDI 0.5 14 1400 1400 1.33 1 26.7 4600 2700 1.24 1.534.2 6000 3400 1.29 2 53.4 7500 5400 1.27 3 61.9 8200 6200 1.18 4 87.610700 8800 1.36 6.5 92.5 18900 9300 1.78

[0139] Block Copolymers Synthesis

[0140] One of the most useful features of a living polymerizationreaction is the ability to synthesize block copolymers. In order toinvestigate the potential to prepare immobilized block copolymerssynthesis of PMMA-b-PBzMA was attempted by a reinitiation experiment.Poly(methyl methacrylate) as prepared immobilized on the Wang resin wasisolated still attached to the resin and combined with a solution oftoluene, catalyst solution and degassed benzyl methacrylate. The mixturewas reheated to 90° C. for 8 hours. Analysis of the cleaved polymer by2D (Differential refractive index and UV detection) SEC showed a bimodalmass distribution with the presence of the residual PMMA macroinitiator.At present the loss of activity has not been overcome and is ascribed toeither termination or deactiviation by oxidation during manipulation.

[0141] In order to overcome this difficulty the second monomer, benzylmethacrylate, was added directly in the reaction medium, without priorbead isolating, after approximately 85-90% conversion of MMA (asdetermined by NMR). This process results in the synthesis of gradientblock copolymers since at least 10% of MMA is polymerized in the secondblock³¹. The SEC trace of this product shows a monomodal, symmetricalpeak with a PDI of 1.2. Moreover, the SEC of the block copolymer withboth UV and refractive index dual detectors gave identical responses(FIG. 6). This indicates the re-growth of the first PMMA block to givecopolymer that contain UV-active chromophores from the aromatic benzylgroup across the entire mass envelope, excellent evidence of theformation of the block copolymer, Table 3. TABLE 3 Block CopolymersPMMA-b-PBzMA. Conver- sion MMA^(a)) Conversion M_(n) NMR M_(n) exp^(c))M_(n) theo^(d)) Run (%) BzMA^(b)) (%) (g.mol⁻¹) (g.mol⁻¹) (g.mol⁻¹) PDI5 80 65 15000 24000 14500 1.10 6 82.5 79.7 22000 34000 20200 1.20 7 93.485.2 28400 39000 22100 1.35

[0142] Residual Copper in Polymers.

[0143] The residual copper content in the polymers was measured usinginductively coupled plasma atomic emission spectroscopy (ICP-AES). Twoanalyses were carried out at different stage: the first one, afterrecovering the polymer attached on the resin and washing the reactionmedium with appropriates solvents and the second one, after cleavagefrom the resin and precipitation of the final polymer in methanol. Thecopper content were 0.039 and 0.001% w/w, respectively, which issignificantly less than the theoretical value of 1.5% w/w if all thecopper remained in the polymer. Thus, the presence of the resin as solidsupport initiator and the possibility offered to easily wash the polymerattached on beads, allow reducing the copper level in the final polymersby approximately 97%.

[0144] Thermal Analysis of Products.

[0145] Thermal analysis by DSC of the final polymers gives someimportant data concerning the arrangement of each block. The blockcopolymer from experiment 7 gave a single glass transition at 76.8° C.(homopolymers have reported Tg's of 100° C. and 54° C. for MMA and BzMArespectively), Figure ?. This indicates shows the homogeneous characterof the block copolymer. The T_(g) value increases when the weightfraction of poly(benzyl methacrylate) decreases to give a single T_(g)at 81.2° C., experiment 6. The predicted T_(g) of 63.6 and 65.5° C.respectively from the Flory equation.

[0146] SEM Study.

[0147] The evolution of the shape of the resin support and particularlythe growth of the polymer around beads was monitored by SEM at differentstages of the polymerization. SEM shows clearly the increase of the sizeof the beads as conversion of MMA increases. For example, 240 μm at 34%to 370 μm for 87.6% of monomer conversion as compared to 150 μm for thestarting material. Moreover, the resin support keeps homogeneous in sizeand distribution all along the polymerization process, which means thatbead behave as a reactor of polymerization. This study revealed alsothat the polymer is covalently attached to the support and growth apartfrom the solid support initiator (see FIG. 9).

[0148] Solid State NMR Study.

[0149]¹H and ¹³C gel-phase NMR have been tried to analyze the resin.This is usually a reliable technique to determine the success or failureof chemical transformations on resin-bound materials. A drawback of the¹³C method is the low sensitivity inherently linked to 1% naturalabundance of ¹³C and to small amount of compound attached to the resin.Consequently, it takes several hours to acquire a spectrum with asuitable signal to noise ratio. The applicability of NMR spectroscopy toresin-supported materials was recently extended through the combinationof efficient swelling conditions and Magic Angle Spinning (MAS)techniques.

[0150] The technique used here is ¹³C Cross Polarization Magic AngleSpinning NMR (¹³C CP/MAS/NMR). This technique has been employed toevaluate the structure of our different compound attached to Wang resinas the initiator, the homopoly(methyl methacrylate) and the copolymerpoly(methyl methacrylate)-b-poly(benzyl methacrylate).

[0151] The MAS NMR technique is a sensitive and nondestructiveanalytical method to completely characterize molecules covalentlyanchored to the solid support.

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1. A supported initiator for transition metal mediated living freeradical and/or atom transfer polymerisation comprising an initiatormoiety attached to a support via a selectively cleavable link.
 2. Asupported initiator according to claim 1, wherein the initiator moietycomprises an activated halogen atom.
 3. A supported initiator accordingto claim 1 or claim 2, wherein the initiator moiety has the formula:R¹⁷R¹⁸R¹⁹C—X wherein: X is selected from Cl, Br, I, OR²⁰, SR²¹, SeR²¹,OP(═O)R²¹, OP(═O)R²¹, OP(═O)(OR²¹)₂, OP(═O)O²¹, O—N(R²¹)₂ andS—C(═S)N(R²¹)₂, where R²⁰=a C₁ to C₂₀ alkyl where one or more of thehydrogen atoms may be independently replaced by halide, R²¹ is aryl or astraight or branched C₁-C₂₀ alkyl group, and where an (NR²¹)₂ group ispresent, the two R²¹ groups may be joined to form a 5- or 6-memberedheterocyclic ring; and R¹⁷, R¹⁸ and R¹⁹ are each independently selectedfrom H, halogen, C₁-C₂₀ alkyl, C₃-C₈ cycloalkyl, C═YR²², C(—Y)NR²³R²⁴,COCl, OH, CN, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, oxiranyl, glycidyl, aryl,heterocyclyl, aralkyl, aralkenyl, C₁-C₆ alkyl in which 1 or morehydrogen atoms are replaced with halogen and C₁ to C₆ allyl substitutedwith from 1 to 3 substitutions selected from alkoxyl, aryl,heterocyclyl, C(═Y)R²², C(═Y)NR²³R²⁴, oxiranyl and glycidyl; where R²²is C₁ to C₂₀ alkyl, C₁ to C₂₀ alkoxy, aryloxy or heterocyclyloxy; andR²³ and R²⁴ are independently H, C, to C₂₀ alkyl, or R²³ and R²⁴ may bejoined together to form an alkylene group of 2 to 5 carbon atoms, thusforming a 3- to 6-membered ring; where Y may be NR²⁵ or O, and R²⁵ is H,straight or branched C₁ to C₂₀ alkyl or aryl; such that no more than twoof R¹⁷, R¹⁸ and R¹⁹ are H, and wherein at least one of R¹⁷, R¹⁸ or R¹⁹is attached to the support, optionally via the selectively cleavablelink.
 4. A supported initiator according to any preceding claim whereinthe initiator moiety is selected from:

 where: R is independently selectable and is selected from straight,branched or cyclic alkyl, hydrogen, substituted alkyl, hydroxyalkyl,carboxyalkyl or substituted benzyl, wherein at least one R is attachedto the support via the selectively cleavable link; and  X is a halide.5. A supported initiator according to any one of claims 1 to 3, whereinthe initiator moiety is 1,1,1-trichloroacetone.
 6. A supported initiatoraccording to any preceding claim, wherein the amount of initiatorloading on the support is 0.01 to 4 mmol g⁻¹, with respect to the totalmass of the support, of initiating sites.
 7. A supported initiatoraccording to any preceding claim, wherein the selectively cleavable linkis an acid-labile link.
 8. A supported initiator according to anypreceding claim, wherein the support is a sheet or bead.
 9. A supportedinitiator according to any preceding claim, wherein the support isinorganic.
 10. A supported initiator according to any preceding claim,wherein the support is a cross-linked organic polymer.
 11. A supportedinitiator according to any preceding claim, wherein the support issolvent swellable.
 12. A supported initiator according to claim 1 havingformula:

where P is a polymeric support.
 13. Use of an initiator according to anypreceding claim in the synthesis of a polymer.
 14. A method forpolymerising one or more olefinicelly unsaturated monomers comprisingthe steps of: (i) providing a supported initiator according to any oneof claims 1 to 12; (ii) reacting the supported initiator with at leastone monomer in the presence of a catalyst to form a polymer attached tothe support; and (iii) removing the support from the polymer by cleavingthe selectively cleavable link.
 15. A method according to claim 14,wherein the polymer is cleaved from the support by cleaving with acid.16. A method according to claims 14 or 15, wherein a gradient polymer isformed by reacting the supported initiator with a first monomer and thenadding a second monomer prior to completion of the polymerisationreaction with the first monomer.
 17. A method according to claims 14 or15, wherein the supported initiator is: (a) reacted with a firstmonomer; (b) any remaining first monomer is removed before terminationof its polymerisation reaction; and. (c) a second monomer is added toform a block copolymer.
 18. A method according to any one of claims 14to 17, wherein the catalyst comprises a ligand which is any N-, O-, P-or S-containing compound which can coordinate in a δ-bond to atransition metal or any carbon-containing compound which can coordinatein a π-bond to the transition metal, such that direct bonds between thetransition metal and growing polymer radicals are not formed.
 19. Amethod according to any one of claims 14 to 17, wherein the catalystcomprises: (a) a first compound MY  where: M is a transition metalhaving an oxidation state which is capable of being oxidised by oneformal oxidation state,  Y is a mono, divalent or polyvalent counterion;and (b) an organodiimine, where at least one of the nitrogens of thediimine is not part of an aromatic ring.
 20. A method according to anyone of claims 14 to 17, wherein the catalyst comprises a first componentof formula: [ML_(m)]^(n+)A^(n−) where: M=a transition metal having anoxidation state which is capable of being oxidised by one formaloxidation state, L=an organodiimine where at least one of the nitrogensof the diimine is not part of an aromatic ring, A=anion, n=integer of 1to 3, m=an integer of 1 to
 2. 21. A method according to any one ofclaims 18 to 20, wherein the transition metal is selected from Cu1+,Cu²⁺, Fe²⁺, Fe³⁺, Ru²⁺, Ru³⁺, Cr²⁺, Cr³⁺, Mo²⁺, Mo³⁺, W²⁺, W³⁺, Mn³⁺,Mn⁴⁺, Rh³⁺, Rh⁴⁺, Re²⁺, Re³⁺, Co⁺, Co²⁺, V²⁺, V³⁺, Zn⁺, Zn²⁺, Au⁺, Au²⁺,Ag⁺ and Ag²⁺.
 22. A method according to claim 14, wherein the catalystis:

with Cu Br
 23. A method according to claim 14 or claim 22, wherein theinitiator has general formula:

where P is a polymeric support.
 24. A method according to any one ofclaims 14 to 24 wherein the amount of initiator loading on the supportis less than 4 mmol g⁻¹ of initiating sites.
 25. A method forsynthesising a supported initiator as defined in any one of claims 1 to12 comprising the steps of: (i) providing a support having one or morereactive groups; and (ii) reacting the support with an initiatorprecursor to form the supported initiator.
 26. A method according toclaim 25 wherein the support has formula: S—OH where S is the supportand the initiator precursor has formula: I-Hal, where I is the initiatorand Hal is a halogen, and the halogen and hydroxyl groups react to formformula: S—O—I
 27. A method according to claim 25 comprising reacting:

to form a supported initiator of formula:

where the arrow indicates the site of the selectively cleavable link.28. A supported initiator according to any one of claims 1 to 12,additionally comprising a polymer extending from the initiator moiety.